Rho Hyunjin, Kim Uijin, Song Jaewhan
Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul 03722, Korea.
BMB Rep. 2025 Aug 4.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex metabolic disorder that encompasses a spectrum of conditions, from simple hepatic steatosis to metabolicassociated steatohepatitis (MASH). MASH is characterized by inflammation and accelerated fibrosis progression, which can ultimately lead to cirrhosis and hepatocellular carcinoma. Given its steadily increasing prevalence, MASLD has emerged as a global health epidemic. Significantly, MASLD represents a stage where liver function can still be partially restored through dietary interventions and physical exercise. However, the longterm sustainability of these lifestyle changes poses a significant challenge. Furthermore, the complex and heterogeneous nature of MASH complicates the development of pharmacotherapeutic strategies and the identification of reliable biomarkers for effective treatment. Therefore, it is essential to gain a comprehensive understanding of the molecular mechanisms driving MASLD and to develop targeted therapeutic interventions. Recent studies have underscored the critical role of posttranslational modifications (PTMs) of proteins in regulating MASLD. PTMs, such as ubiquitination, SUMOylation, Neddylation, and UFMylation, are known to modulate protein function and diverse cellular processes. Among these, ubiquitination is particularly noteworthy for its dual role in mediating protein degradation through the ubiquitin-proteasome system and in regulating cellular signaling pathways in a non-proteolytic manner, depending on the specific linkages formed at the seven distinct lysine residues (K6, K11, K27, K29, K33, K48, and K63) and the Met1-linked (M1) linear ubiquitin chain. Despite significant progress in this area, studies focusing on linkage-specific ubiquitination events that regulate MASLD remain relatively limited. Thus, this review aims to provide a comprehensive summary of the role of linkage-specific ubiquitination in regulating MASLD, as well as exploring other ubiquitinlike modifications that may contribute to its pathophysiology.
代谢功能障碍相关脂肪性肝病（MASLD）是一种复杂的代谢紊乱疾病，涵盖了从单纯性肝脂肪变性到代谢相关脂肪性肝炎（MASH）等一系列病症。MASH的特征是炎症和纤维化进展加速，最终可导致肝硬化和肝细胞癌。鉴于其患病率不断上升，MASLD已成为全球健康问题。重要的是，MASLD代表了一个阶段，在此阶段，通过饮食干预和体育锻炼，肝功能仍可部分恢复。然而，这些生活方式改变的长期可持续性构成了重大挑战。此外，MASH的复杂性和异质性使药物治疗策略的开发以及有效治疗的可靠生物标志物的识别变得复杂。因此，全面了解驱动MASLD的分子机制并开发针对性的治疗干预措施至关重要。最近的研究强调了蛋白质的翻译后修饰（PTM）在调节MASLD中的关键作用。已知泛素化、SUMO化、Neddylation和UFMylation等PTM可调节蛋白质功能和多种细胞过程。其中，泛素化因其在通过泛素-蛋白酶体系统介导蛋白质降解以及以非蛋白水解方式调节细胞信号通路中的双重作用而尤为值得关注，这取决于在七个不同赖氨酸残基（K6、K11、K27、K29、K33、K48和K63）以及Met1连接（M1）的线性泛素链上形成的特定连接。尽管该领域取得了重大进展，但专注于调节MASLD的连接特异性泛素化事件的研究仍然相对有限。因此，本综述旨在全面总结连接特异性泛素化在调节MASLD中的作用，并探索可能对其病理生理学有贡献的其他类泛素修饰。
